The broad long-term objective of this Project is to obtain a fundamental understanding of the basic biophysical and physiological mechanisms of task-induced contrast in human functional magnetic resonance imaging (FMRI). This understanding can be expected to lead to improved FMRI technology, to contribute to knowledge about local control of cerebral hemodynamics, and to provide a basis for the application of FMRI to the field of neuroscience. The hypothesis of this project is that blood oxygen level dependence (BOLD) is the dominant contrast mechanism in susceptibility weighted MR sequences, but that several additional mechanisms associated with task-induced increase in blood flow can give rise to FMRI signals. Three subprojects are proposed to advance this goal. 1) Development of a high-resolution multi-field (0.5, 1.5, and 3 tesla) FMRI test platform consisting of an FMRI brain coil capable of producing strong spatially localized gradients, with four-channel radio- frequency surface coil signal detection. This platform will be used to determine whether FMRI spatial resolution is limited by vessel architecture or the intrinsic signal-to-noise ratio. 2) Biophysical mechanisms of FMRI contrast. A model for FMRI contrast will be developed based on experiments using the test platform of the first subproject. Task-induced changes in the MRI parameters T2 and T2* will be systematically measured as a function of field strength, voxel volume, echo time (TE), and repetition time (TR). Flow-sensitive gradients and out-of-slice saturation will be used to characterize flow effects in FMRI. A particular aim is to arrive at a strategy to localize task-induced FMRI response to the parenchyma, excluding response from arterioles and collecting veins. 3) Physiological mechanisms of FMRI contrast. Studies in both rat and man will be used to test several hypotheses related to those physiological variables that couple FMRI contrast to cerebral activity including blood oxygenation, flow, and perfusion. Experiments will be performed in which somatosensory activation is quantified by cortical evoked potentials, EEG, laser Doppler flowmetry, and cerebral glucose metabolism. The role of cortical set-point, blood flow changes, and hemoglobin saturation on FMRI contrast will be directly assessed. Functional MRI promises to be a truly significant advance toward the goal of understanding brain function, with an enormous potential impact on human health. It is essential that it have a firm foundation that is based on rigorous biophysical and physiological studies.